Pain is one of the most common reasons for a patient to seek medical care and in consequence, pain results in a tremendous number of lost work days per year. There are three general classes of pain: nociceptive pain, neuropathic pain, and psychogenic pain. FIG. 1 illustrates the relationship between different types of pain and conditions affected, such as allodynia and multiple sclerosis.
In nociceptive pain, the stimulation of the sensory nerve endings called nociceptors cause the sensation of pain. Such pain often occurs after injury or surgery. The pain signals are transmitted by the nociceptors to the brain. Often the pain is localised, constant and has an aching or throbbing quality. Once the damage to the tissue heals, the pain usually resolves. Treatment with opioids often resolves nociceptive pain.
Psychogenic pain is a pain disorder that is associated with psychological factors. Some types of mental or emotional problems can cause pain. They can also increase or prolong pain. Headaches, muscle pains, back pain, and stomach pains are some of the most common types of psychogenic pain. People with this pain disorder actually have real pain. The diagnosis is made when all physical causes of pain are ruled out.
Neuropathic pain is the result of an injury or malfunction of the peripheral or the central nervous system. The pain may be triggered by an injury but not necessarily by an injury of the nervous system itself. Neuropathic pain is frequently chronic and is often refractory to treatment with opioids.
Neuropathic pain is caused by abnormalities in the nerves, spinal cord or brain and is a chronic type of non-malignant pain with an estimated prevalence of over 1% of the population. Optimising pain relief in these patients is crucial in helping a patient regain control of his or her life.
The most common cause of neuropathic pain is injury or dysfunction of nerves. Injury or dysfunction of peripheral nerves or nerves descending from the spinal cord results in disinhibition of nerve impulses at the spinal cord which in consequence results in pain. Neuropathic pain can also be centrally mediated, rather than peripheral, in conditions such as spinal cord injury and multiple sclerosis.
Neuropathic pain can therefore be sub-divided into two further classes; peripheral neuropathic pain and central neuropathic pain depending on whether the peripheral or central nervous system is affected.
Patients with peripheral neuropathic pain often experience pain which feels like a burning or electrical pain, whereas others describe their pain as feeling like extreme cold or pins and needles. The pain may be worsened by activity or by wearing clothes over the affected area. The pain may also follow a daily pattern, which may mean it is worse at certain times of the day.
Allodynia is a type of peripheral neuropathic pain. This is a painful response to a typically non-painful stimulus, for example brushing the affected area with a fingertip. The pain tends to increase with repeated stimulation and may spread from the affected area. Allodynic pain can be evoked in response to chemical, thermal (cold or heat) or mechanical low or high intensity stimuli applied either statically or dynamically to skin, joints, bone, muscle or viscera. It is thought that the presence of allodynic pain is a more suitable means of grouping patients suffering from peripheral neuropathic pain than by the specific disease that led to the neuropathic pain.
It is clear that patients who suffer from neuropathic pain can have their quality of life greatly affected by it. The pain can interfere with work and social activities as well as with the amount and quality of sleep that a patient experiences. A successful treatment for the relief of neuropathic pain should improve both the amount of pain that the patient is experiencing as well as improving the patient's quality of life.
The use of pharmaceutical medicaments is the most common treatment for neuropathic pain. Analgesics, antidepressants and anticonvulsants are the drug classes generally in use. The drug carbamezepine, which is an anticonvulsant, is currently the only FDA approved drug which has an indication for neuropathic pain. It has been suggested in post-marketing studies that there is a five- to eight-fold increase in the risk of blood dyscrasias in patients taking carbamezepine. In 7% of patients there has been shown to be a 25% decrease in their white blood cell count.
The use of cannabis as a medicine has long been known and during the 19th Century, preparations of cannabis were recommended as a hypnotic sedative which were useful for the treatment of hysteria, delirium, epilepsy, nervous insomnia, migraine, pain and dysmenorrhoea.
Until recent times the administration of cannabis to a patient could only be achieved by preparation of cannabis by decoction which could then be swallowed, or by the patient inhaling the vapours of cannabis by smoking the dried plant material. Recent methods have sought to find new ways to deliver cannabinoids to a patient including those which bypass the stomach and the associated first pass effect of the liver which can remove up to 90% of the active ingested dose and avoid the patient having to inhale unhealthy tars and associated carcinogens into their lungs.
Formulations containing specific, defined ratios of cannabinoids may be formulated from pure, synthetic or isolated cannabinoids or from extracts derived from the cannabis plant in combination with pharmaceutical carriers and excipients.
Cannabinoids are a group of chemicals known to activate cannabinoid receptors in cells. Phytocannabinoids are the cannabinoids derived from cannabis plants. Endocannabinoids are endogenous cannabinoids found in humans and other animals. The phytocannabinoids can be isolated from plants or produced synthetically. When isolating the phytocannabinoids from plants they can be purified to the extent that all of the other naturally occurring compounds, such as, other minor cannabinoids and plant molecules such as terpenes are removed. This purification results in a purity of greater than 99% (w/w) of the target cannabinoid.
It has been shown previously that the cannabinoid cannabidiol (CBD) administered as a purified compound can partially relieve neuropathic pain (Costa et al., 2004). This was shown using the neuropathic pain model of chronic constriction injury of the rat sciatic nerve and testing the effectiveness of the test article with thermal and mechanical hyperalgesia and mechanical allodynia. These animal models are used to predict the effectiveness of a test compound on neuropathic pain.
More recently the applicant has shown in their granted UK patent, GB2439393, that a plant extract comprising a defined ratio of CBD to THC is more effective at treating peripheral neuropathic pain than the purified components alone. The ratio of CBD to THC which is effective is between 20:1 to 28:1.
The patent application PCT/GB2006/004063 describes the use of an extract of cannabis wherein the THC to CBD ratio is about 1:1. The extract was found to be beneficial in the treatment of peripheral neuropathic pain that is characterised by post-herpetic neuralgia.
Neuropathic pain is often associated with a diverse and complex set of pain stimuli and as such is difficult to treat effectively as the response to treatment is unpredictable.
Surprisingly, the applicants have found that administration of the cannabinoids cannabigerol (CBG), cannabichromene (CBC), cannabidivarin (CBDV) and tetrahydrocannabivarin (THCV) are effective in the treatment of an animal model of neuropathic pain. Since neuropathic pain appears to be refractory to conventional analgesic treatment, such as opiates and non-steroidal anti-inflammatory drugs, the animal studies described herein represents an important finding for clinical settings.